95 results found
Balachandar S, Graves TJ, Shimonty A, et al., 2022, Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations, American Journal of Medical Genetics Part A, Vol: 188, Pages: 959-964, ISSN: 0148-7299
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.
Morton LM, Karyadi DM, Stewart C, et al., 2021, Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident, Science, Vol: 372, ISSN: 0036-8075
The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.
Morton LM, Karyadi D, Stewart C, et al., 2021, Molecular characterization of papillary thyroid cancer in relation to ionizing radiation dose following the Chernobyl accident., Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Bogdanova TI, Saenko VA, Hashimoto Y, et al., 2020, Papillary Thyroid Carcinoma in Ukraine After Chernobyl and in Japan After Fukushima: Different Histopathological Scenarios, THYROID, Vol: 31, Pages: 1322-1334, ISSN: 1050-7256
Mathieson W, Thomas GA, 2020, Why formalin-fixed, paraffin-embedded biospecimens must be used in genomic medicine: an evidence-based review and conclusion., Journal of Histochemistry and Cytochemistry: imaging the spectrum of cell biology, Vol: 68, Pages: 543-552, ISSN: 0022-1554
Fresh-frozen tissue is the "gold standard" biospecimen type for next-generation sequencing (NGS). However, collecting frozen tissue is usually not feasible because clinical workflows deliver formalin-fixed, paraffin-embedded (FFPE) tissue blocks. Some clinicians and researchers are reticent to embrace the use of FFPE tissue for NGS because FFPE tissue can yield low quantities of degraded DNA, containing formalin-induced mutations. We describe the process by which formalin-induced deamination can lead to artifactual cytosine (C) to thymine (T) and guanine (G) to adenine (A) (C:G > T:A) mutation calls and perform a literature review of 17 publications that compare NGS data from patient-matched fresh-frozen and FFPE tissue blocks. We conclude that although it is indeed true that sequencing data from FFPE tissue can be poorer than those from frozen tissue, any differences occur at an inconsequential magnitude, and FFPE biospecimens can be used in genomic medicine with confidence.
Lindberg J, Thomas G, 2020, Making sense of radiation, NUCLEAR ENGINEERING INTERNATIONAL, Vol: 65, Pages: 17-20, ISSN: 0029-5507
Frazer Z, Yoo C, Sroya M, et al., 2020, Effect of different proteinase K digest protocols and deparaffinization methods on yield and integrity of DNA extracted from formalin-fixed, paraffin-embedded tissue, Journal of Histochemistry and Cytochemistry: imaging the spectrum of cell biology, Vol: 68, Pages: 171-184, ISSN: 0022-1554
DNA extracted from formalin-fixed, paraffin-embedded tissue sections is often inadequate for sequencing, due to poor yield or degradation. We optimized the proteinase K digest by testing increased volume of enzyme and increased digest length from the manufacturer’s protocol using 54 biospecimens, performing the digest in centrifuge tubes. Doubling the quantity of proteinase K resulted in a median increase in yield of 96%. Applying the optimized proteinase K protocol to sections deparaffinized on microscope slides generated a further increase in yield of 41%, but only at >50,000 epithelial tumor cells/section. DNA yield now correlated with (χ2 = 0.84) and could be predicted from the epithelial tumor cell number. DNA integrity was assayed using end point multiplex PCR (amplicons of 100–400 bp visualized on a gel), quantitative PCR (qPCR; Illumina FFPE QC Assay), and nanoelectrophoresis (DNA Integrity Numbers [DINs]). Generally, increases in yield were accompanied by increases in integrity, but sometimes qPCR and DIN results were conflicting. Amplicons of 400 bp were almost universally obtained. The process of optimization enabled us to reduce the percentage of samples that failed published quality control thresholds for determining amenability to whole genome sequencing from 33% to 7%.
Thomas G, 2019, Expert response: Gerry Thomas on behalf of the Chernobyl tissue bank, BIOPRESERVATION AND BIOBANKING, Vol: 17, Pages: 515-515, ISSN: 1947-5535
Mathieson W, Thomas G, 2019, Using FFPE Tissue in Genomic Analyses: Advantages, Disadvantages and the Role of Biospecimen Science, CURRENT PATHOBIOLOGY REPORTS, Vol: 7, Pages: 35-40
Bogdanova T, Zurnadzhy L, Masiuk S, et al., 2019, Histopathological characteristics and post-operative follow-up of patients with potentially radiogenic papillary thyroid carcinoma depending on oncocytic changes availability in the tumor cells., Exp Oncol, Vol: 41, Pages: 235-241, ISSN: 1812-9269
AIM: To compare the frequency of main histopathological characteristics, 131І thyroid radiation doses, invasive properties and post-operative follow-up of patients of different age groups with potentially radiogenic papillary thyroid carcinoma (PTC) with the presence and absence of oncocytic changes in tumor cells. MATERIALS AND METHODS: PTC removed in 483 patients from high risk age-group for radiogenic thyroid cancer development (children and adolescents at the time of Chornobyl accident who lived in the northern regions of Ukraine: Kyiv, Zhytomyr, and Chernihiv regions) have been studied microscopically. RESULTS: The frequency of PTC with the presence of oncocytic changes (OCh) in tumor cells increased significantly with increasing of patients' age at the time of surgery: from 8.3% in children 4-14 years old to 54.3% in adults 39-48 years old (ptrend < 0.0001). The presence of such changes is associated with papillary and solid-trabecular dominant tumor growth pattern in more than 90% of cases in each age group. The mean 131І thyroid dose in the whole series of PTC patients with OCh was significantly lower compared to the same index in PTC patients without OCh (493.7 mGy and 765.8 mGy, respectively, p < 0.0001). In addition, regional metastases recurrences were revealed more frequently in patients with OCh in primary PTC compared with patients without OCh in primary tumor (7.2% vs 1.5%, p = 0.0022). CONCLUSIONS: Significantly increasing age-trend of OCh in PTC of patients affected by the Chornobyl fallout and operated at age from 4 to 48 years, as well as opposite decreasing linear age-trend of 131І thyroid dose may reflect a gradual increase of sporadic PTCs frequency in the potentially radiogenic series with time elapsed since accident. The frequency of oncocytic insensitive to radioiodine therapy of lymph node metastases recurrences also increased with patients age and OCh availability in primary PTC.
Thomas G, 2018, RADIATION AND THYROID CANCER-AN OVERVIEW, RADIATION PROTECTION DOSIMETRY, Vol: 182, Pages: 53-57, ISSN: 0144-8420
Togawa K, Ahn HS, Auvinen A, et al., 2018, Long-term strategies for thyroid health monitoring after nuclear accidents: recommendations from an Expert Group convened by IARC, Lancet Oncology, Vol: 19, Pages: 1280-1283, ISSN: 1470-2045
Bogdanova TI, Saenko VA, Brenner AV, et al., 2018, Comparative Histopathologic Analysis of "Radiogenic" and "Sporadic" Papillary Thyroid Carcinoma: Patients Born Before and After the Chernobyl Accident, THYROID, Vol: 28, Pages: 880-890, ISSN: 1050-7256
Amrania H, Woodley-Barker L, Goddard K, et al., 2018, Mid-infrared imaging in breast cancer tissue: an objective measure of grading breast cancer biopsies, Convergent Science Physicsl Oncology, Vol: 4, ISSN: 2057-1739
Introduction: -The majority of cancers are diagnosedusingexcised biopsy specimens. These are graded, using a gold-standard histopathology protocol based onhaemotoxylin and eosin (“H+E”)chemical staining. Howeverthe grading is done by eye and if the same biopsy is graded by differentpractitioners, they typically only agree ~70% of the time. The resultingovertreatment problem constitutes a massive unmet need worldwide.Objective:-Ournew ‘Digistain’technology, uses mid-infrared imaging to mapthe fractional concentration of nucleic acids, i.e. the nuclear-to-cytoplasmic chemical ratio (NCR) across an unstained biopsy section. It allows a quantitative “Digistain index” (DI) score, corresponding to the NCR, to be reproducibly extracted from an objective physical measurement of a cancer. Our objective here is to evaluate itspotential for aiding cancer diagnosis for the first time. We correlate the DI scores with H+E grades in a double-blind clinical pilot trial.Methods:-Two adjacent slices were taken from 75 breast cancer FFPE blocks; one was graded with the standard H+E protocol, and also used to define a “Region of Interest” (RoI). Digistain was then used to acquire a DI value averaged over the corresponding RoI on the other (unstained) sliceand theresults werestatistically analysed.Results:-We find the DI score correlates significantly (p=0.0007) with tumorgradein a way that promises to significantly reduce the inherent subjectivity and variability in biopsy grading.Discussion: The NCR is elevated by increased mitotic activity because cells divide when they are youngerand, on average, becomesmaller asthe disease progresses. Also, extra DNA and RNA is generated as thenuclear transcription machinery goes awry and nuclear pleomorphism occurs. Both effects make the NCR a recognized biomarker for a wide range of tumors
Mathieson W, Guljar N, Sanchez I, et al., 2018, Extracting DNA from FFPE Tissue Biospecimens Using User-Friendly Automated Technology: Is There an Impact on Yield or Quality?, BIOPRESERVATION AND BIOBANKING, Vol: 16, ISSN: 1947-5535
DNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissue blocks is amenable to analytical techniques, including sequencing. DNA extraction protocols are typically long and complex, often involving an overnight proteinase K digest. Automated platforms that shorten and simplify the process are therefore an attractive proposition for users wanting a faster turn-around or to process large numbers of biospecimens. It is, however, unclear whether automated extraction systems return poorer DNA yields or quality than manual extractions performed by experienced technicians. We extracted DNA from 42 FFPE clinical tissue biospecimens using the QiaCube (Qiagen) and ExScale (ExScale Biospecimen Solutions) automated platforms, comparing DNA yields and integrities with those from manual extractions. The QIAamp DNA FFPE Spin Column Kit was used for manual and QiaCube DNA extractions and the ExScale extractions were performed using two of the manufacturer's magnetic bead kits: one extracting DNA only and the other simultaneously extracting DNA and RNA. In all automated extraction methods, DNA yields and integrities (assayed using DNA Integrity Numbers from a 4200 TapeStation and the qPCR-based Illumina FFPE QC Assay) were poorer than in the manual method, with the QiaCube system performing better than the ExScale system. However, ExScale was fastest, offered the highest reproducibility when extracting DNA only, and required the least intervention or technician experience. Thus, the extraction methods have different strengths and weaknesses, would appeal to different users with different requirements, and therefore, we cannot recommend one method over another.
Sanchez I, Betsou F, Culot B, et al., 2018, RNA and microRNA Stability in PAXgene-Fixed Paraffin-Embedded Tissue Blocks After Seven Years' Storage., American Journal of Clinical Pathology, Vol: 149, Pages: 536-547, ISSN: 0002-9173
Objectives: To evaluate the stability of RNA and microRNA (miRNA) in PAXgene-fixed paraffin-embedded tissue blocks after 7 years' storage. Methods: RNA and miRNA were extracted from PAXgene-fixed paraffin-embedded (PFPE) blocks in 2009 then stored at -80°C. Seven years later, RNA and miRNA were again extracted from the same blocks. RNA and miRNA integrity in the 2009 and 2016 extractions were compared using RNA integrity number (RIN), paraffin-embedded RNA metric (PERM), reverse transcription polymerase chain reaction (RT-PCR) for different amplicon lengths, and quantitative RT-PCR (qRT-PCR) for three mRNA and three miRNA targets. Results: In PFPE blocks, mRNA was poorer in 2016 extractions compared to the 2009 extractions in all blocks and all assays applied, with transcripts degrading at different rates in the same blocks. For miRNA, qRT-PCR showed no statistically significant differences between 2009 and 2016 extractions. Conclusions: mRNA in PFPE tissue blocks degrades at room temperature storage over 7 years.
McLean AR, Adlen EK, Cardis E, et al., 2017, A restatement of the natural science evidence base concerning the health effects of low-level ionizing radiation., Proceedings of the Royal Society B: Biological Sciences, Vol: 284, ISSN: 1471-2954
Exposure to ionizing radiation is ubiquitous, and it is well established that moderate and high doses cause ill-health and can be lethal. The health effects of low doses or low dose-rates of ionizing radiation are not so clear. This paper describes a project which sets out to summarize, as a restatement, the natural science evidence base concerning the human health effects of exposure to low-level ionizing radiation. A novel feature, compared to other reviews, is that a series of statements are listed and categorized according to the nature and strength of the evidence that underpins them. The purpose of this restatement is to provide a concise entrée into this vibrant field, pointing the interested reader deeper into the literature when more detail is needed. It is not our purpose to reach conclusions on whether the legal limits on radiation exposures are too high, too low or just right. Our aim is to provide an introduction so that non-specialist individuals in this area (be they policy-makers, disputers of policy, health professionals or students) have a straightforward place to start. The summary restatement of the evidence and an extensively annotated bibliography are provided as appendices in the electronic supplementary material.
Leonard RCF, Adamson DJA, Bertelli G, et al., 2017, GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial, Annals of Oncology, Vol: 28, Pages: 1811-1816, ISSN: 0923-7534
BackgroundChemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women’s health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone agonist during chemotherapy for early breast cancer reduced the risk of POI.Patients and methodsThis was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I–IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI.ResultsA total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Müllerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups.ConclusionThis study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be dete
McKenzie GAG, McFarlane T, Hing S, et al., 2017, Novel Mutations in Sinonasal Squamous Cell Carcinoma Detected Using Next Generation Sequencing, 106th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP), Publisher: NATURE PUBLISHING GROUP, Pages: 329A-329A, ISSN: 0893-3952
Saenko VA, Thomas GA, Yamashita S, 2017, Meeting report: the 5th International expert symposium in Fukushima on radiation and health, Environmental Health, Vol: 16, ISSN: 1832-3367
BACKGROUND: The symposium entitled "Chernobyl +30, Fukushima +5: Lessons and Solutions for Fukushima's Thyroid Question" was held in September, 2016 in Fukushima. The aim of the Symposium was to revisit and recapitulate evidence from the studies in Chernobyl in order to share multidisciplinary opinions and views on the likely reason for the high rate of thyroid cancer detected by the Thyroid Ultrasound Examination program in Fukushima Prefecture. PARTICIPANTS AND MATTERS DISCUSSED: The high prevalence of thyroid cancer in young individuals causes concerns among Fukushima residents and the general public that it might be due to putative radiation exposure from the Fukushima Daiichi Nuclear Power Plant accident. Twenty-six experts from Japan and abroad, including participants affiliated with international organizations, reviewed the results of radiation epidemiology investigations in Chernobyl, presented clinical experience of diagnosis, treatment and follow-up of patients with radiation-related thyroid cancer, and scrutinized the findings on thyroid cancer in Fukushima. CONCLUSION: Conclusions drawn at the symposium included understanding that in contrast to Chernobyl, doses to the public from the accident in Fukushima were too low to give rise to a discernible excess risk for thyroid cancer. The high detection rate of thyroid cancer and benign abnormalities resulted from the use of highly sensitive ultrasound equipment and sophisticated protocol of examination used in the Thyroid Ultrasound Examination, and therefore not attributable to radiation. Coordinated efforts will be necessary to avoid overdiagnosis and overtreatment, which may carry its own health disbenefits. Clear communication to the screening participants and their families is recommended in regard to why the examination is being conducted and to explain the likely outcomes and risks, including the means and options for treatment if a thyroid disorder is detected.
Cardoso F, van't Veer LJ, Bogaerts J, et al., 2016, 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer, New England Journal of Medicine, Vol: 375, Pages: 717-729, ISSN: 1533-4406
BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. RESULTS: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. CONCLUSIONS: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the r
Mathieson W, Marcon N, Antunes L, et al., 2016, A Critical Evaluation of the PAXgene Tissue Fixation System Morphology, Immunohistochemistry, Molecular Biology, and Proteomics, American Journal of Clinical Pathology, Vol: 146, Pages: 25-40, ISSN: 1943-7722
Objectives: To evaluate the PAXgene tissue fixation system.Methods: Clinical biospecimens (n = 46) were divided into PAXgene-fixed paraffin-embedded (PFPE), formalin-fixed paraffin-embedded (FFPE), and fresh-frozen (FF) blocks. PFPE and FFPE sections were compared for histology (H&E staining) and immunohistochemistry (14 antibodies) using tissue microarrays. PFPE, FFPE, and FF samples were compared in terms of RNA quality (RNA integrity number, polymerase chain reaction [PCR] amplicon length, and quantitative reverse transcription PCR), DNA quality (gel electrophoresis and methylation profiling) and protein quality (liquid chromatography-mass spectrometry [LC-MS/MS]).Results: PFPE protocol optimization was required in most cases and is described. RNA extracted from PFPE sections was considerably less degraded than that from FFPE sections but more degraded than that from FF blocks. Genomic-length DNA was extracted from PFPE and FF biospecimens, and methylation profiling showed PFPE and FF biospecimens to be almost indistinguishable. Only degraded DNA was extracted from FFPE biospecimens. PFPE sections yielded peptides that were slightly less amenable to LC-MS/MS analysis than FFPE sections, but FF gave slightly better results.Conclusions: While it cannot be envisaged that PAXgene will replace formalin in a routine clinical setting, for specific projects or immunodiagnostics involving biospecimens destined for immunohistochemical or histologic staining and DNA or RNA analyses, PAXgene is a viable option.
Anderson R, Adamson D, Yellowlees A, et al., 2016, Administration of a GnRH agonist during chemotherapy for breast cancer reduces ovarian toxicity in women aged under 40 years, Publisher: OXFORD UNIV PRESS, Pages: 339-339, ISSN: 0268-1161
Mathieson W, Betsou F, Myshunina T, et al., 2016, The effect of long-term -80°C storage of thyroid biospecimens on RNA quality and ensuring fitness for purpose., Journal of Clinical Pathology, ISSN: 0021-9746
AIMS: To establish whether RNA degrades in long-term storage at -80°C and whether RNA integrity numbers (RINs) determine 'fitness for purpose' in severely degraded RNA. METHODS: RNA was extracted from 549 thyroid biospecimens stored at -80°C for 0.1-10.9 years then their RINs correlated with storage time. RT-PCR for 65, 265, 534 and 942 base pair amplicons of hydroxymethylbilane synthase was used to measure amplicon length in RNA from cryopreserved and FFPE biospecimens that were equally degraded according to RIN. RESULTS: Storage time did not correlate with RIN. Longer amplicons were obtained from cryopreserved samples than FFPE samples with equal RINs. CONCLUSIONS: RNA does not degrade in thyroid biospecimens stored for long periods of time at -80°C. Although RINs are known to predict amenability to analytical platforms in good quality samples, this prediction is unreliable in severely degraded samples.
Thomas GA, Symonds P, 2016, Radiation Exposure and Health Effects - is it Time to Reassess the Real Consequences?, Clinical Oncology, Vol: 28, Pages: 231-236, ISSN: 0936-6555
Our acceptance of exposure to radiation is somewhat schizophrenic. We accept that the use of high doses of radiation is still one of the most valuable weapons in our fight against cancer, and believe that bathing in radioactive spas is beneficial. On the other hand, as a species, we are fearful of exposure to man-made radiation as a result of accidents related to power generation, even though we understand that the doses are orders of magnitude lower than those we use everyday in medicine. The 70th anniversary of the detonation of the atomic bombs in Hiroshima and Nagasaki was marked in 2015. The 30th anniversary of the Chernobyl nuclear power plant accident will be marked in April 2016. March 2016 also sees the fifth anniversary of the accident at the Fukushima nuclear power plant. Perhaps now is an opportune time to assess whether we are right to be fearful of the effects of low doses of radiation, or whether actions taken because of our fear of radiation actually cause a greater detriment to health than the direct effect of radiation exposure.
Wilson C, Gossiel F, Leonard R, et al., 2016, Goserelin, as an ovarian protector during (neo)adjuvant breast cancer chemotherapy, prevents long term altered bone turnover, Journal of Bone Oncology, Vol: 5, Pages: 43-49, ISSN: 2212-1366
Handkiewicz-Junak D, Swierniak M, Rusinek D, et al., 2016, Gene signature of the post-Chernobyl papillary thyroid cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 43, Pages: 1267-1277, ISSN: 1619-7089
PurposeFollowing the nuclear accidents in Chernobyl and later in Fukushima, the nuclear community has been faced with important issues concerning how to search for and diagnose biological consequences of low-dose internal radiation contamination. Although after the Chernobyl accident an increase in childhood papillary thyroid cancer (PTC) was observed, it is still not clear whether the molecular biology of PTCs associated with low-dose radiation exposure differs from that of sporadic PTC.MethodsWe investigated tissue samples from 65 children/young adults with PTC using DNA microarray (Affymetrix, Human Genome U133 2.0 Plus) with the aim of identifying molecular differences between radiation-induced (exposed to Chernobyl radiation, ECR) and sporadic PTC. All participants were resident in the same region so that confounding factors related to genetics or environment were minimized.ResultsThere were small but significant differences in the gene expression profiles between ECR and non-ECR PTC (global test, p < 0.01), with 300 differently expressed probe sets (p < 0.001) corresponding to 239 genes. Multifactorial analysis of variance showed that besides radiation exposure history, the BRAF mutation exhibited independent effects on the PTC expression profile; the histological subset and patient age at diagnosis had negligible effects. Ten genes (PPME1, HDAC11, SOCS7, CIC, THRA, ERBB2, PPP1R9A, HDGF, RAD51AP1, and CDK1) from the 19 investigated with quantitative RT-PCR were confirmed as being associated with radiation exposure in an independent, validation set of samples.ConclusionSignificant, but subtle, differences in gene expression in the post-Chernobyl PTC are associated with previous low-dose radiation exposure.
McArdle I, Fare C, Bearpark M, et al., 2015, Research Data Management 'Green Shoots' Pilot Programme, Final Reports, Research Data Management 'Green Shoots' Pilot Programme, Final Reports
This document contains the final reports of six Research Data Management "Green Shoots" projects run at Imperial College in 2014.
Thomas G, 2015, Don't let fear win, NEW SCIENTIST, Vol: 227, Pages: 26-27, ISSN: 0262-4079
Di Maro G, Salerno P, Unger K, et al., 2014, Anterior gradient protein 2 promotes survival, migration and invasion of papillary thyroid carcinoma cells, Molecular Cancer, Vol: 13, ISSN: 1476-4598
Background: Through a transcriptome microarray analysis, we have isolated Anterior gradient protein 2 (AGR2) as agene up-regulated in papillary thyroid carcinoma (PTC). AGR2 is a disulfide isomerase over-expressed in severalhuman carcinomas and recently linked to endoplasmic reticulum (ER) stress. Here, we analyzed the expression ofAGR2 in PTC and its functional role.Methods: Expression of AGR2 was studied by immunohistochemistry and real time PCR in normal thyroidsand in PTC samples. The function of AGR2 was studied by knockdown in PTC cells and by ectopic expressionin non-transformed thyroid cells. The role of AGR2 in the ER stress was analyzed upon treatment of cells,expressing or not AGR2, with Bortezomib and analyzing by Western blot the expression levels of GADD153.Results: PTC over-expressed AGR2 at mRNA and protein levels. Knockdown of AGR2 in PTC cells inducedapoptosis and decreased migration and invasion. Ectopic expression of AGR2 in non-transformed human thyroid cellsincreased migration and invasion and protected cells from ER stress induced by Bortezomib.Conclusions: AGR2 is a novel marker of PTC and plays a role in thyroid cancer cell survival, migration, invasion andprotection from ER stress.
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